Ornithine transcarbamylase (OTC) deficiency is a urea cycle defect with varying frequency and severity of episodes of hyperammonemia. We report three patients with OTC deficiency with recurrent pancreatitis. The pathogenesis of acute pancreatitis in this patient population requires further elucidation. Pancreatitis significantly affected dietary/metabolic management and increased frequency of hospitalizations.
[Show abstract][Hide abstract] ABSTRACT: We investigated respiratory chain (RC), tricarboxylic acid cycle (TCA) enzyme activities, and oxidative stress in the tissues of six patients with organic aciduria (OA) presenting various severe complications to further document the role of mitochondrial OXPHOS dysfunction in the development of complications. Two children with propionic acidemia (PA), presenting a severe cardiomyopathy, and four with methylmalonic aciduria (MMA), who developed a neurologic disease (3/4) and renal failure (2/4), were followed. We measured RC and TCA cycle enzyme activity in patient tissues and assessed oxidative metabolism in fibroblasts in vitro. Various RC deficiencies were found in tissues of patients with PA and MMA. TCA cycle enzyme activities were normal when investigated and reactive oxygen species were decreased as well as detoxifying systems activities in the two patients tested. In conclusion, mitochondrial dysfunction was found in all investigated tissues of six patients with organic acidemia presenting with severe complications. Reactive oxygen species production and detoxification were decreased in fibroblast primary cultures. Our results bring further support for a role of secondary respiratory deficiency in the development of late multiorgan complications of these diseases.
Pediatric Research 05/2009; 66(1):91-5. DOI:10.1203/PDR.0b013e3181a7c270 · 2.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hereditary pancreatitis is a rare cause of chronic pancreatitis. The prevalence was evaluated to 0.3/100000 in Western Countries. Genetic disorders are due to mutations of the PRSS1 gene on the long arm of the chromosome 7, encoding for the cationic trypsinogen. The inheritance pattern is autosomal dominant with an incomplete penetrance (80%). Since 1996, more than 30 mutations were found. The three more common mutations are R122H, N29I and A16V. First symptoms begin since childhood, mainly before 10 years old. Main symptoms are pancreatic pain and acute pancreatitis (>70%). CP morphological changes as pancreatic calcifications are diagnosed at a median age of 22-25 years. Exocrine and endocrine pancreatic insufficiency occurred in 34% and 26% at a median age of 29 and 38 years. No clinical differences exist according to the mutation type. No excess of mortality in hereditary pancreatitis population compared to general population was found, despite a real risk of cancer. The cumulative risks of pancreatic cancer at 50, 60 and, 75 years are 10%, 18.7% and, 53.5%, respectively. The relative risk of cancer increases in smokers and is evaluated to 8.55. Hereditary pancreatitis diagnosis permits to propose an adapted management in expert centres.
[Show abstract][Hide abstract] ABSTRACT: The causes of chronic (CP) and recurrent acute pancreatitis (RAP) in children include anatomic abnormalities and hereditary, metabolic, and autoimmune disorders, with a significant proportion of cases being labeled as idiopathic. Genetic pancreatitis (GP) is associated with mutations of cystic fibrosis transmembrane conductor regulator gene (CFTR), cationic trypsinogen (PRSS1) gene, and serine protease inhibitor Kazal type 1 (SPINK1). There literature is sparse regarding the clinical profile of GP in children. The aim of the present study was to estimate the prevalence and describe the clinical characteristics and outcome of genetic pancreatitis.
We reviewed the charts of children ages 18 years or younger with RAP or CP diagnosed from 2000 to 2009 at the Children's Hospital of Wisconsin, Milwaukee. Twenty-nine patients with RAP or CP were identified, of whom 23 (79%) were positive for mutations in ≥1 of the above-mentioned genes, and were included for review.
The median age of symptom onset was 5 years (range 9 months-15 years) with diagnosis at 6.5 years (range 1-16 years). Twenty-one were white; 14 were girls. The most common presenting symptoms were abdominal pain and vomiting. Patients with RAP had 2 to 8 episodes of pancreatitis during 3.6-year average follow-up. Family history was positive in 5 of 29 of gene-tested patients. CFTR, SPINK1, or PRSS1 mutations were seen in 14 (48%), 8 (27%), and 7 (24%) patients, respectively. Two patients were homozygous for CFTR mutations, 6 heterozygote and 4 patients had 5 T variants. Two other patients had double heterozygous mutations in F508 del/2789 + 5G > A and F508 del/5T variant. Six patients with CP had a combination of CFTR and SPINK1 or PRSS1 mutations. Eleven of 29 (38%) patients met radiological criteria for CP. All of the heterozygote patients with a combination of CFTR and SPINK1 or PRSS1 mutations had CP. Eight patients developed a chronic pain syndrome and 2 developed exocrine pancreatic insufficiency during follow-up.
We found a high prevalence of genetic mutations in patients without anatomic or metabolic abnormalities known to be associated with pancreatitis. Studies are needed to ascertain the genetic causes of RAP and CP and examine the relation between single CFTR mutations and single mutations in the PRSS1 and SPINK1 genes.
Journal of pediatric gastroenterology and nutrition 11/2011; 54(5):645-50. DOI:10.1097/MPG.0b013e31823f0269 · 2.63 Impact Factor
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